Interaction between Apoptotic Pathways and Regeneration in the Myocardium

Loren Field

Indiana University School of Medicine
Wells Center, Krannert Institute
702 Barnhill Drive, Indianapolis, Indiana, 46260

Many forms of cardiac disease are precipitated by either acute or chronic cardiomyocyte death. Although it is accepted that there is some capacity for cardiomyocyte DNA synthesis in the adult heart, the degree to which this occurs and the cellular consequences (e.g., polyploidization, karyokinesis, and/or cytokinesis) have been the subject of considerable debate. It has also been suggested that cardiomyogenic adult stem cells may contribute to myocardial reconstitution, but again the degree to which this occurs is currently controversial. The potential contribution of cell fusion events to apparent stem cell-mediated cardiomyogenesis also needs to be resolved. Despite data supporting the presence of at least some degree of myocardial renewal via either proliferation or stem cell recruitment, the propensity for cardiomyocyte loss in cardiovascular disease indicates that the rate at which renewal occurs naturally is insufficient to reverse many disease processes. Interventions aimed at augmenting cardiomyocyte number in diseased hearts therefore could be of considerable therapeutic value. Current strategies to accomplish this include cellular transplantation, adult stem cell mobilization, and cardiomyocyte cell cycle activation. We have been interested in the identifying pathways that can activate cell cycle activity in terminally differentiated cardiomyocytes, with the hope that subsequent proliferation of cardiomyocytes will suffice to regenerate lost myocardial tissue. Several transgenic models with targeted expression of cell cycle regulatory genes that mediate apparent cardio-regenerative growth will be presented. Additionally, data suggesting that relaxation of apoptotic pathways may be sufficient to permit cardiomyocyte cell cycle re-entry will be discussed.